While functional neuroimaging has made great inroads in neuroscience, the applications of functional Magnetic Resonance Imaging (fMRI) to the study of cigarette addiction have been limited. The applicants believe that this is the consequence, in large part, of technical issues that include the difficulty of creating a normal smoking environment (or even of administering cigarette smoke), and the unknown direct effects of the many components of cigarette smoke on the overall sensitivity of the imaging experiments (most of which depend on vascular effects for their signal). In the preliminary studies, The applicants have developed an approach to cigarette smoke delivery that is fully compatible with fMRI and can deliver much of the normal smoking experience during an imaging session. The applicants have shown that this device can mimic important features of normal smoking, including changes in CO, behavioral satisfaction and nicotine blood level. The applicants also demonstrate that we can examine brain signal changes during smoking and have a means to compare fMRI activation signals before and after smoking. In the research plan that follows, the applicants propose to characterize fully the psychological and physiological effects achieved with our in-magnet smoking device and to study carefully the fMRI activations before, during and after smoking. Further, in order to distinguish between effects of nicotine and smoking per se and to facilitate future experiments, the applicants will study these changes after smoking of normal (NIC+) and reduced nicotine (NIC-) cigarettes. With these data in hand, the applicants should be well positioned to use fMRI to probe many outstanding questions in the neurobiology of compulsive smoking. For example, what specific brain regions are involved in craving and its satisfaction by cigarette use? What is the neural basis for the changes in cognitive task performance that characterize withdrawal? What brain areas mediate the separable component effects of nicotine and other aspects of cigarette smoking? What physiological factors underlie shifts in brain lateralization associated with smoking and abstinence? The methods developed in this grant will give scientists new tools for exploring these questions; the answers they find may help to develop new treatments for nicotine addiction and to understand why some individuals are more vulnerable to this life-threatening disorder.